INTRODUCTION: Vasomotor function is diminished in the resistance vasculature with old age which compromises local tissue hemodynamic regulation and is characterized in most cases by blunted vasodilator and vasoconstrictor reactivity. Empagliflozin (EMPA), a drug commonly employed to treat diabetes, possesses pleiotropic effects such as reducing cardiovascular mortality. Recent evidence suggests a direct role of EMPA in ameliorating age-related vascular dysfunction via sodium-glucose co-transporter 2 inhibition (SGLT2i). Most studies focus on chronic in vivo EMPA treatment; however, very little is known regarding acute SGLT2i and vascular function in vitro. The objective of this investigation was to determine the effects of acute SGLT2i on arteriolar vasoreactivity and interrogate the vasomotor pathway specificity in mesenteric arterioles from young and old mice. We hypothesized that SGLT2i would ameliorate age-related vasomotor dysfunction in mesenteric arterioles. METHODS: First order arterioles (1A) from the mesentery of young (4-6 mo old; n=8) and old (24-26 mo old; n=10) male C57BL/6 mice were isolated, cannulated, and pressurized at 68 cmH 2 O. In mesenteric 1As, vasodilatory and vasoconstrictor responses to increasing concentrations of isotonic potassium chloride (KCl; 10-100 mM) were assessed in the absence and presence of EMPA (1 µM). Thereafter, arterioles were incubated with barium chloride (BaCl2; 100 mM), an inward rectifying K + (KIR) channel inhibitor, and KCl responses were repeated. RESULTS: KCl-induced vasodilation and vasoconstriction were lower in old vs young arterioles (P0.05). CONCLUSION: These data suggest that aging compromises K + -mediated vasoreactivity in the mesenteric microcirculation. In young mesenteric arterioles, SGLT2 appears to contribute mechanistically to normal K + -mediated vasoreactivity. Interestingly, in mesenteric arterioles from old mice, SGTL2i improved K + -mediated vasodilation and decreased K + -mediated vasoconstriction. These data suggest that SGLT2i improves age-related deficits in vasodilation, but not vasoconstriction, to extracellular K + in the mesenteric vasculature and may be dependent in part on KIR channel activation. Further, the reduced vasoconstrictor reactivity with SGLT2i appears to be vasomotor pathway specific, as EMPA treatment did not impact vasoconstriction to PE. Alterations in SGLT2 expression or function/activity may contribute mechanistically to age-associated decrements in K + -mediated vasodilation of mesenteric arterioles. FUNDING: Nora Eccles Treadwell Foundation; Ruth L. Kirschstein National Research Service Award (NRSA) Institutional Research Training Grant: T32HL007576 (AGH); National Institute on Aging: R01 AG077751 (AJD, LAL), R01 AG076748 (LAL); VA Special Fellowship in Geriatrics (KMS). This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Horn et al. (Fri,) studied this question.